PROJECT SUMMARY HAND remains among the most debilitating features of chronic infection with HIV, despite almost universal use of and success of antiretroviral therapy in controlling HIV replication and preventing immunodeficiency and AIDS. The pathophysiological mechanisms of HAND are not well understood, and there are no effective treatments. Growing evidence supports insulin-mediated signaling pathways as key components in normal cognitive processes. Dysregulation of insulin signaling is implicated in inflammatory processes and energy metabolism and associated with the pathogenesis of several neurodegenerative diseases, including HAND. Recent clinical studies have shown that intranasal delivery of insulin to the CNS enhances cognitive processes in normal, Alzheimer?s and diabetic patients. The overall hypothesis of this P01 is that chronic intranasal insulin administration may also be effective in improving cognitive deficits in HAND. In this project we will explore this hypothesis preclinically by testing whether intranasal insulin administration dose dependently increases brain insulin levels, and attenuates cognitive and histological deficits in the EcoHIV murine model of HAND with antivetroviral therapy. We will also monitor energy metabolism, lipid profiles, insulin signaling, and selected markers of neuroinflammation. Collectively these data will provide guidance on the insulin brain exposure and biomarker exploration in the HAND clinical investigations through new information on insulin brain pharmacokinetics and characterization of CSF markers indicative of insulin efficacy. Such exposure-response and biomarker data may prove useful beyond HAND, including future studies in metabolic and other neurodegenerative diseases.